Hypercholesterolemia is a condition in mammals that can induce monocytes to migrate into the arterial wall and mature into foam cells or tissue macrophages that accumulate fatty material including cholesterol esters. The accumulation of foam cells thickens the inner lining of the artery and forms atherosclerotic plaques or lesions containing cholesterol, smooth muscle cells, and connective tissue cells. Affected arteries lose elasticity and become narrowed or obstructed by the plaques. Furthermore, atherosclerotic plaques may collect calcium, become brittle, and even rupture, triggering the formation of a blood clot or thrombus capable of occluding an artery and causing a stroke or a heart attack. In addition to the arteries of the brain and heart, atherosclerosis may affect the arteries of the arms, legs, kidneys, and other vital organs.
Lipoxygenases are enzymes that catalyze the oxidation of polyunsaturated fatty acids such as the low-density lipoproteins related to cholesterol and necessary for foam cell formation. For example, 15-lipoxygenase (15-LO) oxidizes esterified polyenoic fatty acids. 15-LO has been implicated in inflammatory disorders and in the origin and recruitment of foam cells (see, e.g., Harats, et al., Trends Cardiovasc. Med., 1995;59(1):29-36). In addition to modifying lipoproteins relating to the formation of foam cells, 15-LO also mediates an inflammatory reaction in the atherosclerotic lesion. In human monocytes, 15-LO is induced by the cytokine IL-4.
Inhibitors of 15-LO are therefore useful to prevent and treat inflammatory diseases such as asthma, psoriasis, osteoarthritis, rheumatoid arthritis, colorectal cancer, and atherosclerosis. For example, Sendobry, et al., British J. of Pharmacology, 1977;120:1199-1206 show suppression of atherogenesis in rabbits fed a high-fat diet and treated with a 15-LO inhibitor.
Numerous indole and benzimidazole compounds are known, and many are said to be useful as antiinflammatory agents. For example, Gastpar et al. describe a series of indole anticancer agents, J. Med Chem., 1998;41:4965-4972. Connor et al. describe certain 2-phenyl benzimidazoles as antiinflammatory agents (WO 98/06703). Cornicelli et al. describe both indole and benzimidazole antiinflammatory agents in U.S. Pat. No. 6,001,866.
An object of this invention is to provide new indole and benzimidazole compounds that are potent inhibitors of 15-LO.